Exercise intolerance and endothelial dysfunction are hallmarks of type 2 diabetes (T2D) and chronic heart failure (CHF) and are powerful prognostic indicators of future hospitalization and death. Over 5.7 million Americans have CHF. One in five will die within one year of diagnosis, and survival rates are much lower for the nearly 40% of patients who have concomitant T2D. Endothelial function is a critical determinant of exercise capacity. During exercise, shear stress stimulates production of nitric oxide (NO) from the endothelium, leading to vasodilation and redistribution of blood flow to working muscles. This process is impaired in T2D and CHF and correlates strongly with exercise capacity at baseline and in response to exercise training in patients with CHF. Aerobic exercise training improves endothelial function and exercise capacity in patients with T2D or CHF. However, exercise capacity is reduced in patients with combined CHF+T2D relative to those with CHF alone, and preliminary evidence suggests gains in exercise capacity in response to exercise training are also attenuated in this population. Oxidative stress is high in CHF and T2D and is commonly implicated as a key mediator of reduced NO bioavailability and endothelial function. We hypothesize that when added to the complications of CHF, the metabolic and vascular perturbations of T2D augment production of reactive oxygen species (ROS), further limiting NO bioavailability and endothelial function. We propose to measure exercise capacity, skeletal muscle perfusion during exercise (near-infrared spectroscopy), endothelial function (brachial artery flow-mediated dilation), NO bioavailability (nitrite flux) and ROS (nitrotyrosine, 8-OHdG) i patients with CHF (n=30) or CHF+T2D (n=30) prior to and following a 12- week exercise training program (5d/wk, 30 min/d, 60-75% VO2max) to determine whether: 1) lower exercise capacity in CHF+T2D is associated with diminished skeletal muscle perfusion during exercise, NO bioavailability, endothelial function, and greater ROS production relative to patients with CHF alone, and 2) improvements in exercise capacity in response to exercise training are mitigated in patients with CHF+T2D and are associated with attenuated improvements in endothelial function and skeletal muscle blood flow during exercise. The proposed studies will be a first step in providing valuable insight into the mechanisms underlying reduced exercise capacity in patients with CHF+T2D, mechanisms which may lead to the development and testing of targeted interventions to augment endothelial function and exercise capacity or may point toward pharmacologic interventions that will subsume the same functions. This project will also provide the applicant with the opportunity to learn new laboratory skills including Doppler ultrasound, near infrared spectroscopy, and measures of plasma nitrite flux while refining those needed for the conduct of clinical exercise intervention trials in patient populations as well as grant writing, manuscript preparation, and statistical analysis. PUBLIC HEALTH RELEVANCE: Exercise intolerance and endothelial dysfunction are hallmarks of type 2 diabetes (T2D) and chronic heart failure (CHF) and are powerful prognostic indicators of future hospitalization and death. Although aerobic exercise training improves endothelial function and exercise capacity in patients with T2D or CHF, exercise capacity is reduced in patients with combined CHF+T2D relative to those with CHF alone, and preliminary evidence suggests gains in exercise capacity in response to exercise training are also attenuated in this population. The proposed studies will be a first step in providing valuable insight into the mechanisms underlying reduced exercise capacity in patients with CHF+T2D, mechanisms which may lead to the development and testing of targeted interventions to augment endothelial function and exercise capacity.